Ischemic brain injury such as stroke is a leading cause of neurological disability and death in the States. There is, however, no effective strategy to protect the brain from ischemic injury. Recently, we have made exciting observations on effect of electro-acupuncture (EA) on cerebral ischemia. The most striking finding is that EA remarkably reduces brain infarction due to the occlusion of middle cerebral artery, which is dependent on the EA-triggered cellular/molecular events in the brain. Since our studies and those of others have shown that 1) activation of delta-opioid receptor (DOR) attenuates hypoxic/ischemic disruption of ionic homeostasis that triggers neuronal apoptosis and death; 2) DOR up-regulation enhances intracellular survival signals; 3) opioid receptor activation inhibits inflammatory responses, e.g., production of inflammatory cytokines that plays a critical role in ischemic injury; and 4) DOR inhibition largely attenuates the EA-induced protection against ischemic injury, it is likely that the EA-induced protection represents the outcome of cellular and molecular regulation at multiple levels in the brain. Specifically, it may depend on DOR up-regulation and the DOR-mediated stabilization of ionic homeostasis and modulation of survival/death signals. The general hypothesis of this proposal is that EA protects against cerebral ischemia mainly through DOR up-regulation and the DOR-mediated modulation of cellular and molecular signaling in neurons.. With molecular, transgenic and electrophysiological approaches, this proposal is designed to accomplish 3 specific aims: 1) to investigate if EA protects the brain from cerebral ischemia via DOR up-regulation; 2) to investigate if the EA protection is mediated by DOR-based stabilization of ionic homeostasis; and 3) to investigate if the EA protection relies on DOR-mediated inhibition of inflammatory responses to ischemia. The outcome data of this project may yield important information on the mechanism underlying the EA-induced protection from cerebral ischemia and may provide novel clues for therapeutic solutions of stroke.